Assessment of nociception and related quality-of-life measures in a porcine model of neurofibromatosis type 1

Rajesh Khanna, Aubin Moutal, Katherine A. White, Aude Chefdeville, Pedro Negrao De Assis, Song Cai, Vicki J. Swier, Shreya S. Bellampalli, Marissa D. Giunta, Benjamin W. Darbro, Dawn E. Quelle, Jessica C. Sieren, Margaret R. Wallace, Christopher S. Rogers, David K. Meyerholz, Jill M. Weimer

    Research output: Contribution to journalArticlepeer-review


    Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder resulting from germline mutations in the NF1 gene, which encodes neurofibromin. Patients experience a variety of symptoms, but pain in the context of NF1 remains largely underrecognized. Here, we characterize nociceptive signaling and pain behaviors in a miniswine harboring a disruptive NF1 mutation (exon 42 deletion). We present the first characterization of pain-related behaviors in a pig model of NF1, identifying unchanged agitation scores, lower tactile thresholds (allodynia), and decreased response latencies to thermal laser stimulation (hyperalgesia) in NF11/ex42del (females only) pigs. Male NF11/ex42del pigs with tumors showed reduced sleep quality and increased resting, 2 healthrelated quality-of-life symptoms found to be comorbid in people with NF1 pain. We explore these phenotypes in relationship to suppression of the increased activity of the N-Type voltage-gated calcium (CaV2.2) channel by pharmacological antagonism of phosphorylation of a regulatory protein the collapsin response mediator protein 2 (CRMP2), a known interactor of neurofibromin, and by targeting the interface between the a subunit of CaV2.2 and the accessory b-subunits with small molecules. Our data support the use of NF11/ex42del pigs as a large animal model for studying NF1-Associated pain and for understanding the pathophysiology of NF1. Our findings demonstrate the translational potential of 2 small molecules in reversing ion channel remodeling seen in NF1. Interfering with CaV2.2, a clinically validated target for pain management, might also be a promising therapeutic strategy for NF1-related pain management.

    Original languageEnglish (US)
    Pages (from-to)2473-2486
    Number of pages14
    Issue number11
    StatePublished - Nov 1 2019


    • CRMP2 modifications
    • Cyclin-dependent kinase 5 phosphorylation
    • NF1
    • NF11/ex42del
    • Neurofibromatosis type 1
    • Pain
    • Porcine
    • Sleep quality
    • Genes, Neurofibromatosis 1/physiology
    • Pain/pathology
    • Male
    • Calcium Channels, N-Type/genetics
    • Neurofibromin 1/genetics
    • Ganglia, Spinal/metabolism
    • Animals
    • Neurons/metabolism
    • Nociception/physiology
    • Swine
    • Quality of Life
    • Hyperalgesia/metabolism

    ASJC Scopus subject areas

    • Clinical Neurology
    • Neurology
    • Anesthesiology and Pain Medicine


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